Abstract Lung cancer in never smokers (LCINS) is a disease and disparity that disproportionately affects Asian American (AA) females. In contrast to declining incidence trends seen among most racial/ethnic groups, incidence of lung cancer, especially adenocarcinoma, has been increasing in most AA ethnic groups. The majority of AA females, upwards of nearly 90% among Chinese, diagnosed with lung cancer have never smoked. There is very little known of the contributing risk factors to the high and increasing incidence rates of LCINS among AA females, particularly as risk factors identified in studies in Asia may have limited significance among AA populations. Moreover, there is limited understanding of the relationships between the mutational signatures of tumors among this population and their associated risk factors. Such information will improve our understanding of the underlying potential mechanistic pathways. Thus, the overall objective of this study is to identify the attributable risk of known, putative, and suspected risk factors for lung cancer among AA female never smokers. Recognizing that currently there are no U.S. datasets nor existing cohorts with data for evaluating putative and suspected risk factors that may be most relevant to this population, we propose a robust, population-based case-control study, leveraging early-case ascertainment methods from cancer registries and tested state-of-the-science approaches for unbiased control ascertainment. With high- quality, multilevel data collected from an estimated 600 female AA never-smoker lung cancer cases and 600 ethnicity and age frequency-matched controls, we aim to: Aim 1a. Identify risk factors for LCINS among AA females, with attention to differences by histology and EGFR (epidermal growth factor receptor) status (determined using whole exome sequencing [WES]), and focusing on multi-level factors including: a) genetic ancestry; b) individual- level exposures, including putative and suspected risk factors; and c) contextual-level risk factors including indoor and ambient air pollutants and the social environment, with consideration of nativity and years in the U.S. versus Asia; Aim 1b. Determine the independent and joint contributions of multi-level risk factors to LCINS among AA females by calculating the attributable risk for each risk factor, individually and in total; Aim 2a. Characterize the mutational landscape of LCINS among AA females, through WES of paired tumor-normal tissue samples to define somatic mutation profiles, mutational signatures, and EGFR status of LCINS AA females; and Aim 2b. Identify multi- level risk factors associated with the major mutational tumor features. All aims will assess potential differences by EGFR status. The proposed research will involve the assembly of the largest population-based lung cancer case- control dataset, with associated genetic and tumor genomic data, for never-smoking AA women. It will provide a first- ever opportunity to evaluate detailed multilevel factors contributing to the lung cancer disparity in distinct AA ethnic groups. A clear understanding of the etiologic factors underlying the high and increasing lung cancer risk among AA never-smoker females is necessary for designing the appropriate prevention strategies to reduce their high burden of disease.